Rising hospitalization costs have led to an intensified effort to identify biological markers for endogenous psychiatric disorders. The availability of specific markers would permit more rapid diagnoses and promote the use of appropriate treatments, thereby reducing patient suffering and health care costs two candidates for a trait-marker of endogenous depression are serotonin (5HT) uptake and imipramine (IMI) binding by blood platelets. Originally thought to reflect a common biological defect, these measures are now believed to quantify distinct, although related phenomenon. A number of studies have both supported, and refuted claims that platelet models are trait-markers. The discrepancies between these reports may be due to variability resulting from a strong age dependence of binding, and a prominent seasonal rhythm of both binding and 5HT uptake. The present study is a unique attempt to evaluate the platelet models while controlling both confounding variables. The experimental approach is to compare platelet measurements from patients, prior to, and during, antidepressant treatment. Patients who remain on treatment will also be compared with a group switched to placebo. The effects of age and circannual rhythms will be controlled by expressing patient values on a percent control basis. Control values will be obtained by multiple regression of platelet measures, age, and date data obtained by repeated measurements of a normal control group over the course of the year. The present study differs from previous studies in its use of a normalized design rather than a reliance upon large sample numbers to reduce variance. The results should provide definative answers to questions concerning potential trait, state, and drug dependent changes in platelet measures.